IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses
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ABSTRACT:
PROVIDER: PRJNA483401 | ENA |
REPOSITORIES: ENA
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Project description:Type I interferons (IFN) induce powerful anti-viral and innate immune responses via the transcription factor, IFN-stimulated gene factor (ISGF3). However, in some pathological contexts type I IFNs are responsible for exacerbating inflammation. Here, we show that a high dose of IFN-β also activates an inflammatory gene expression program in contrast to IFN-λ3, a type III IFN, which elicits only the common anti-viral gene program. We show that the inflammatory gene program depends on a second, potentiated phase in ISGF3 activation. Iterating between mathematical modeling and experimental analysis we show that the ISGF3 activation network may engage a positive feedback loop with its subunits IRF9 and STAT2. This network motif mediates stimulus-specific ISGF3 dynamics that are dependent on ligand, dose, and duration of exposure, and when engaged activates the inflammatory gene expression program. Our results reveal a previously underappreciated dynamical control of the JAK-STAT/IRF signaling network that may produce distinct biological responses, and suggest that studies of type I IFN dysregulation, and in turn therapeutic remedies, may focus on feedback regulators within it.
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Project description:Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.
2019-06-12 | GSE120944 | GEO
Project description:Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.
2019-06-12 | GSE120943 | GEO
Project description:Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.
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Project description:Interferon-induced transmembrane protein (IFITM1) plays a dual role in restriction of RNA viruses and in metastatic cancer cell growth. The signal transduction events that are orchestrated by IFITM1 are not well defined. We set out to identify IFITM1 interacting proteins to begin to define its mechanism of action. Affinity purification of SBP-tagged IFITM1, coupled to SWATH-mass spectrometry, identified significantly higher confidence interacting proteins from IFN- treated cells, relative to non-treated cells. This promoted an examination of the protein synthetic machinery in order to determine whether IFITM1 can impact on ribosomal proteome from IFN- treated cells. Isogenic ifitm1 null and ifitm1-ifitm3 null-SiHa cell panels were generated using CRISPR gRNAs to define signaling events that are linked to IFN--dependent protein synthesis. Ultracentrifugation sedimentation of cell lysates from interferon gamma treated wt and ifitm1-ifitm3 null-SiHa cells was carried out to isolate ribosomal constituents. Although SWATH-mass spectrometry of the 40S, 60S, and 80S fractions demonstrated changes in selected protein content, a significant reduction in A254 (RNA) in the 80S ribosomal fractions suggested a relatively select defect in 80S ribosomal biogenesis in ifitm1-ifitm3 null cells. The localization of IFITM1 to ribosomal protein components prompted an analysis of IFN--dependent protein synthesis using pulse SILAC. STAT1 and B2M were two dominant proteins whose synthesis increased equivalently in wt or ifitm1-ifitm3 null cells. However, MHC class I molecules and ISG15 were the most highly suppressed IFN--responsive proteins in the ifitm1-ifitm3 double null cells and this was confirmed using ifitm1 single null cells. Transient depletion of IFITM1 using targeted siRNA also depleted MHC class I molecules as well as IFITM3, STAT1, B2M, and ISG15. These data have implications for the function of IFITM1 in mediating IFN--stimulated protein synthesis and associated antigen presentation during either oncogenic or anti-viral signalling.
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Project description:Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.
2019-06-20 | GSE130567 | GEO